Workshop on Pharmaceutical Engineering for Undergraduate

Engineering Education

Stephanie Farrell, Zenaida Otero Gephardt, Mariano J. Savelski, C. Stewart Slater,

Department of Chemical Engineering Rowan University

Glassboro, New Jersey

Session 1a

2012 ASEE Summer School for ChE Faculty

Orono, ME July 21-26, 2012

Workshop Goals• Present essential elements of pharmaceutical

engineering relevant to a ChE

• Describe methods of curricular enhancement through:

– Homework problems/illustrative examples

– Demonstrations

– Laboratory experiments

– Course integration into introductory ChE courses

• Additional learning resources through compendium of

educational materials and pharmaceutical education site:

www.PharmaHUB.org

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Workshop Agenda• Introduction• Primer on Pharmaceutical Engineering• Drug Manufacture (Mixing operations)• Drug Delivery• Problem Sets in Pharma Eng• Pharma Life Cycle Analysis tutorial• PharmaHUB tutorial

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Background

• Most Introductory ChE educational materials focus on traditional aspects of chemical processing

• New technology can be adapted and introduced when basic concepts are taught within the context of existing courses

• Need to prepare students for graduate education/research: medicine, bio-eng, pharma engineering and careers in the field

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NSF ERC-SOPS• Rowan is an Outreach Partner institution

of the ERC – Structured Organic Particulate Systems (Rutgers lead institution)

• The Center’s research focus is on pharmaceutical processing which include: manufacturing science; composites structuring and characterization; and particle formation and functionalization

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Primer on Pharmaceutical Industry

• Major commercial sector in U.S. and worldwide

• Major employer in MidAtlantic region

• Prepare ChEs for roles in:– R&D

– Process Design/Engineering

– Manufacturing

– Environmental/Health/Safety

Sustainability

– Regulatory Affairs

– Marketing and Sales 6

• The pharmaceutical industry’s main goal is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases*

• API (Active Pharmaceutical Ingredient)– The compound within the pill or solution that

treats the disease

• $331.3 billion in U.S. pharmaceutical sales - 2011**

• Highly regulated by Federal government (FDA, DEA)

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* Bristol-Myers Squibb Mission Statement (www.bms.com) 2012** Business Monitor International. United States Pharmaceuticals and Healthcare Report Q2 2012. March 2012.

Worldwide Pharmaceutical Industry

Image from: J. Cacciotti and P. Clinton. “The Lull Between Two Storms.” Pharmaceutical Executive. 2010.

2010

Five of the top-ten companies are based in the United States:#1 Pfizer, #4 Merck, #8 Johnson & Johnson, #9 Eli Lilly, #10 Abbot

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• Top selling prescription drug (2011) was Lipitor® (Pfizer) with global sales of $10.7 billion– But this goes off-patent in 2012 and will be

manufactured generically

• Generic market is expanding worldwide

• Top selling over the counter (OTC) drug category (2010) is “cough/cold related” drugs with U.S. sales of $4.05 billion

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K. Stone. “Top Branded Drug Sales for 2011.” http://pharma.about.com/od/Sales_and_Marketing/tp/Top-Branded-Drug-Sales-For-2011.htm. Viewed June 2012

“OTC Sales by Category -- 2007-2010.” Consumer Healthcare Products Association. http://www.chpa-info.org/pressroom/Sales_Category.aspx. Viewed 2012.

Drug Development Timeline• 7-11 years between development and

manufacture – Regulatory steps (Phase I-III)• 10% success rate for new drug development• Once process is approved by FDA, any

changes are hard to implement

10ChEs involved in R&D/scale-up/manufacture

Drug Development Attrition Rate

11Glasser and Pedersen, Pharmaceutical Bulk Drug Production, ERC Educational Modules, www.pharmaHUB.org/resources/286, 2009Original source: Merck

Takes >$800 Mil to develop a new drug

Pharmaceutical Manufacture

API Manufacture

“Bulk” Pharmaceutical

Production Steps –Reaction and Purification Processes

Drug Formulation Drug Delivery

Drug Manufacture Processes to Formulate API into Dosage

Raw materials: Reactants, etc.

Solvents

Drug Delivery into Body

Energy

Waste

API

Energy

Excipients

Waste

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API Manufacture

• Natural product isolation• Biotechnology / biochemical

synthesis (“large” molecule API)• Organic synthesis (“small”

molecule API)

Terminology• Transformation = Reaction step• Isolation = Separation or

Purification step13

API Manufacture• Drugs manufactured in a batch process• Typical range of amounts produced depends

on the drug potency and sales projections• Widely prescribed drugs >100’s MT/yr*• The batch processing steps will be repeated

over and over again (“campaigns”) to produce the amount of API needed for annual drug production

*1 metric ton (MT) = 1,000 kg 14

S = Solvent – vary in number and complexity for each stepR = Reactant – vary in number and complexity for each stepI = IntermediateAPI = Active Pharmaceutical Ingredient

Typical Drug Synthesis – “Campaigns”

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• Multi-step synthesis, transformations – Intermediate compounds• Isolations (purification)

ReactionCrystallization/

Recrystallization

Filtration or Wash Step

DIstillation

R-1API

WasteWaste

I-1 I-1

Crystallization/Recrystallization

I-5I-5

S-16R-5 S-15S-2S-1

Filtration

Waste

S-17

I-5

Reaction

I-1I-5

Slater, Savelski, Carole, Constable, Green Chemistry in the Pharmaceutical Industry, Wiley-VCH, Germany, 49-82, 2010

Manufacturing Issues• Batch-based processes

• Extensive use of multiple organic solvents and reagents – varying degrees of toxicity

• Waste generated and emission over life cycle

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Crystallization

Filtration Reaction

Distillation

Extraction

Storage

Mixing

Top Ten SolventsMethanol n-Butyl alcoholDichloromethane N-methyl-2-pyrrolidone Toluene N,N-DimethylformamideAcetonitrile AmmoniaChlorobenzene Formic acid

2008 TRI Releases for the Pharma sectorSlater, Savelski, Carole, Constable, Green Chemistry in the Pharmaceutical Industry, Wiley-VCH, Germany, 49-82, 2010

• Solid/Liquid processing – centrifugation, filtration, drying- Wastes generated- Fugitive emissions- Solids handling- Dust explosion potential

• Purity vs. yield• Outsourcing process steps

Manufacturing Issues

Specialty Chem. Co. B

Drug ManufacturerFine Chem. Co. A

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Slater, Savelski, Carole, Constable, Green Chemistry in the Pharmaceutical Industry, Wiley-VCH, Germany, 49-82, 2010

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Magnitude of Scale

Lab Scale~10 g API~100 mL vessel

Pilot Plant Scale~20 - 200 kg API~200 - 2000 L vessel

Manufacturing Scale>1000 kg API (1 metric ton)>10,000 L vessel

Discovery

Clinical Trials

Manufacturing

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Drug Formulation Processes

• Batch processes are typically used– Blending/mixing, milling/grinding, drying, etc

• API is blended with various “excipients”– Fillers, binders, lubricants, flavors, colors, . . .

• Unlike API synthesis, drug formulation usually involves solid phase components– Solid phase mixtures – tablets & capsules

• Particle size and particle interaction are important factors

Robson, Scientific Computing World, 2007

Raw materials

Oven drying

Blending

Granulation

Milling

CompressionCoating

Lubrication

Finished products

Filtration /drying Crystallization

Excipients

Drug Formulation

20Adapted from: Glasser and Pedersen, Pharmaceutical Bulk Drug Production, ERC Educational Modules, www.pharmaHUB.org/resources/286, 2009

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Drug Delivery Methods

Glasser and Pedersen, Pharmaceutical Bulk Drug Production, ERC Educational Modules, www.pharmaHUB.org/resources/286, 2009

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ERC-SOPS Novel Dosage Formation

• Research underway at NSF-ERC (www.ercforsops.org) at Rutgers University

• Pharmaceutical plant of the future could be a personalized compact device, such as a modified ink-jet printer

• Formulary of multiple drugs in cassette form– Greatly reduced facilities cost– Reduced batch size– Reduce wasted product– Personalized dosage based on weight– On-site use for military, emergency response, developing

countries

Muzzio, ERC-SOPS Annual Meeting, Rutgers University, Piscataway, NJ, Dec 2006

Acknowledgements

• NSF ERC for Structured Organic Particulate Systems: grant # 0540855

• Rutgers University– Henrik Pederson, Center Director – Education

– Aisha Lawrey, Center Associate Director – Education, Outreach and Diversity

• U.S. Environmental Protection Agency: grant #NP97212311-0

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